Abstract We previously reported that primary neuronal cells treated with apolipoprotein E (apoE) or an apoE-derived peptide (EP) increased ERK activation and decreased JNK activation via apoE receptors. Here, we examined if the effects observed in vitro were observed in vivo. Similar to our observations in primary neurons, in vivo we found that injections of 2 μM EP into the rat hippocampus increased the levels of ERK activation and decreased JNK activation. However, the time course of these effects was slower in vivo. Immunohistochemical analysis of the tissue showed prominently increased ERK phosphorylation and decreased JNK phosphorylation in neuronal cells throughout the hippocampus, particularly in the CA3 regions. To determine if apoE was endocytosed by neurons, we conjugated fluorescent microspheres with the EP and injected them into the rat hippocampus. After 7 days, the microspheres were present in neurons. We also examined the in vivo effects of apoE on ApoEr2 and APP processing. EP and full-length apoE3 and apoE4 increased C-terminal fragments of ApoEr2 and APP after a single injection, multiple injections, and chronic infusion paradigms. ApoE3 produced higher levels of ApoEr2 and APP C-terminal fragments than apoE4. These results demonstrate that apoE alters ApoEr2 and APP processing in vivo. The increase in ERK activation is consistent with a role for apoE in a neuronal response to stress, and the decrease in JNK activation suggests that apoE may have anti-apoptotic effects, over several days.